In the present description the term “alkyl”, alone or in combination with other groups, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one to ten carbon atoms.
The term “lower alkyl” or “C1-C8-alkyl”, alone or in combination, signifies a straight-chain or branched-chain alkyl group with 1 to 8 carbon atoms, preferably a straight or branched-chain alkyl group with 1 to 6 carbon atoms and particularly preferred a straight or branched-chain alkyl group with 1 to 4 carbon atoms. Examples of straight-chain and branched C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls, preferably methyl and ethyl and most preferred methyl.
The term “lower alkenyl” or “C2-C8-alkenyl”, alone or in combination, signifies a straight-chain or branched alkyl group comprising an olefinic bond and up to 8, preferably up to 6, particularly preferred up to 4 carbon atoms. Examples of alkenyl groups are ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and isobutenyl. A preferred example is 2-propenyl.
The term “alkoxy” refers to the group R′—O—, wherein R′is alkyl. The term “lower alkoxy” refers to the group R′—O—, wherein R′ is lower alkyl and the term “lower alkyl” has the previously given significance. Examples of lower alkoxy groups are e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec. butoxy and tert.butoxy, preferably methoxy and ethoxy and most preferred methoxy.
The term “lower alkoxyalkyl” or “alkoxy-C1-C8-alkyl” refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by an alkoxy group as defined above. Among the preferred lower alkoxyalkyl groups are methoxymethyl, methoxyethyl and ethoxymethyl, with methoxymethyl being especially preferred.
The term “halogen” refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.
The term “lower halogenalkyl” or “halogen-C1-C8-alkyl” refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a halogen atom, preferably fluoro or chloro, most preferably fluoro. Among the preferred halogenated lower alkyl groups are trifluoromethyl, difluoromethyl, fluoromethyl and chloromethyl, with trifluoromethyl being especially preferred.
The term “lower halogenalkoxy” or “halogen-C1-C8-alkoxy” refers to lower alkoxy groups as defined above wherein at least one of the hydrogen atoms of the lower alkoxy group is replaced by a halogen atom, preferably fluoro or chloro, most preferably fluoro. Among the preferred halogenated lower alkyl groups are trifluoromethoxy, difluoromethoxy, fluormethoxy and chloromethoxy, with trifluoromethoxy being especially preferred.
The term “lower hydroxyalkyl” or “hydroxy-C1-C8-alkyl” refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a hydroxy group. Examples of lower hydroxyalkyl groups are hydroxymethyl or hydroxyethyl.
The term “cycloalkyl” or “C3-C7-cycloalkyl” means a cycloalkyl ring containing 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The cycloalkyl ring may be optionally substituted as defined herein. Especially preferred is cyclopropyl.
The term “lower cycloalkylalkyl” or “C3-C7-cycloalkyl-C1-C8-alkyl” refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a cycloalkyl group as defined above. Examples of preferred lower cycloalkylalkyl groups are cyclopropylmethyl or cyclopropylmethyl wherein the cyclopropyl group is substituted by lower alkyl, lower hydroxyalkyl or lower alkoxyalkyl, preferably methoxymethyl.
The term “heterocyclyl” means a monovalent saturated or partly unsaturated ring incorporating one, two, or three heteroatoms chosen from nitrogen, oxygen or sulfur. The heterocyclyl ring may be optionally substituted as defined herein. Examples of heterocyclyl moieties include azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dihydropyridyl, piperidyl, piperazinyl, morpholinyl, or thiomorpholinyl, azepinyl, dihydropyrrolyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl or tetrahydropyranyl. Especially preferred are oxetanyl, piperidyl and morpholinyl.
The term “lower heterocyclylalkyl” or “heterocyclyl-C1-C8-alkyl” refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a heterocyclyl group as defined above. An examples of a preferred lower heterocyclylalkyl group is 3-fluorooxetan-3-yl.
The term “a 4-, 5-, 6- or 7-membered saturated or partly unsaturated heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur” refers to a saturated or partly unsaturated N-heterocyclic ring, which may optionally contain a further nitrogen, oxygen or sulfur atom, such as 2,5-dihydropyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, or 3,6-dihydro-2H-pyridinyl. The heteroyclic ring may be unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen.
The term “carbamoyl” refers to the group —CO—NH2.
The term “pharmaceutically acceptable salts” refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. In addition these salts may be prepared form addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polymine resins and the like. The compound of formula I can also be present in the form of zwitterions. Particularly preferred pharmaceutically acceptable salts of compounds of formula I are the hydrochloride salts.
The compounds of formula I can also be solvated, e.g. hydrated. The solvation can be effected in the course of the manufacturing process or can take place e.g. as a consequence of hygroscopic properties of an initially anhydrous compound of formula I (hydration). The term pharmaceutically acceptable salts also includes physiologically acceptable solvates.
“Isomers” are compounds that have identical molecular formulae but that differ in the nature or the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereoisomers”, and stereoisomers that are non-superimposable mirror images are termed “enantiomers”, or sometimes optical isomers. A carbon atom bonded to four nonidentical substituents is termed a “chiral center”.
In detail, the present invention relates to compounds of the general formula
wherein    R1 is selected from the group consisting of hydrogen,    lower alkyl, lower alkenyl,    cycloalkyl or lower cycloalkylalkyl, wherein the cycloalkyl ring may be unsubstituted or substituted by one or two groups selected from the group consisting of lower alkyl, lower hydroxyalkyl and lower alkoxyalkyl,    lower hydroxyalkyl,    lower alkoxyalkyl, and    lower heterocyclylalkyl, wherein the heterocyclyl ring may be unsubstituted or substituted by one or two groups selected from lower alkyl and halogen;    R2 is selected from the group consisting of hydrogen,    lower alkyl, lower alkenyl,    cycloalkyl or lower cycloalkylalkyl, wherein the cycloalkyl ring may be unsubstituted or substituted by one or two groups selected from the group consisting of lower alkyl, lower hydroxyalkyl and lower alkoxyalkyl,    lower hydroxyalkyl,    lower alkoxyalkyl, and    lower heterocyclylalkyl, wherein the heterocyclyl ring may be unsubstituted or substituted by one or two groups selected from lower alkyl and halogen; or    R1 and R2 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered saturated or partly unsaturated heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, said saturated or partly unsaturated heterocyclic ring being unsubstituted or substituted by one, two or three groups independently selected from the group consisting of lower alkyl, halogen, halogenalkyl, cyano, hydroxy, hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl;A is selected from
wherein    m is 0, 1 or 2;    R3 is lower alkyl;    n is 0, 1 or 2;    R7 is lower alkyl;    p is 0, 1 or 2;    q is 0, 1 or 2;    R5 is hydrogen or lower alkyl;    and pharmaceutically acceptable salts thereof.
Preferred compounds of formula I according to the present invention are those, wherein R1 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, cycloalkyl, lower cycloalkylalkyl, wherein the cycloalkyl ring may be unsubstituted or substituted by one or two groups selected from lower alkyl, lower hydroxyalkyl or lower alkoxyalkyl, lower hydroxyalkyl, lower alkoxyalkyl, and lower heterocyclylalkyl, wherein the heterocyclyl ring may be unsubstituted or substituted with one or two groups selected from lower alkyl or halogen, and R2 is hydrogen or lower alkyl.
More preferred are compounds of formula I according to present invention, wherein R1 is selected from the group consisting of lower alkyl, cycloalkyl, lower cycloalkylalkyl, wherein the cycloalkyl ring may be unsubstituted or substituted by lower alkoxyalkyl, lower alkoxyalkyl, and lower heterocyclylalkyl wherein the heterocyclyl ring may be unsubstituted or substituted with one or two groups selected from lower alkyl or halogen, and R2 is hydrogen or lower alkyl.
Especially preferred are those compounds of formula I, wherein R1 and R2 are lower alkyl.
Another group of preferred compounds of formula I according to present invention are those, wherein R1 and R2 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered saturated or partly unsaturated heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, said heterocyclic ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, halogenalkyl, cyano, hydroxy, hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl.
Preferred compounds of formula I are those, wherein R1 and R2 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered saturated or partly unsaturated heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, said heterocyclic ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, halogenalkyl, cyano, hydroxy, lower alkoxy, oxo, phenyl, benzyl, pyridyl and carbamoyl.
More preferred are those compounds of formula I, wherein R1 and R2 together with the nitrogen atom to which they are attached form a 4-, 5-, or 6- or 7-membered saturated or partly unsaturated heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, said heterocyclic ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, halogenalkyl, cyano, hydroxy, lower alkoxy, and oxo.
Even more preferred are compounds of formula I, wherein R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of morpholine, piperidine, 2,5-dihydropyrrole, pyrrolidine, azepane, piperazine, azetidine, thiomorpholine and 3,6-dihydro-2H-pyridine, said heterocyclic ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, halogen, halogenalkyl, cyano, hydroxy, lower alkoxy, and oxo.
Especially preferred are compounds of formula I, wherein R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, 3,6-dihydro-2H-pyridinyl, piperidinyl, 2-methylpiperidinyl, 3-methylpiperidinyl, 4-hydroxypiperidinyl, 4,4-difluoropiperidinyl, 2,5-dihydropyrrolyl, 4-methylpiperidinyl, pyrrolidinyl, 2-methylpyrrolidinyl, 2-trifluoromethylpyrrolidinyl, 2-cyanopyrrolidinyl, 3-hydroxypyrrolidinyl and azetidinyl.
Furthermore, compounds of formula I according to the present invention, wherein A signifies
and wherein m is 0, 1 or 2, and R3 is lower alkyl, are preferred.
Within this group, those compounds of formula I are preferred, wherein m is 0, thus meaning pyrrolidine groups are preferred.
A further preferred group includes those compounds of formula I, wherein m is 1, thus meaning piperidine groups are also preferred.
Also preferred are compounds of formula I according to the present invention, wherein A signifies
and wherein n is 0, 1 or 2; and R4 is lower alkyl, with those compounds, wherein n is 0, thus meaning pyrrolidine derivatives, being more preferred.
Further preferred compounds of formula I according to the present invention are those, wherein A signifies
wherein p is 0, 1 or 2, q is 0, 1 or 2, and R5 is hydrogen or lower alkyl.
Within this group, those compounds of formula I are preferred, wherein p is 1, thus meaning piperidine groups are preferred. Especially preferred are those compounds of formula I, wherein p is 1 and q is 1.
Furthermore, compounds wherein R5 is hydrogen, are preferred.
Examples of preferred compounds of formula I are the following:    [6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-(4-methoxy-piperidin-1-yl)-methanone,    (2,5-dihydro-pyrrol-1-yl)-[6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-methanone,    6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid ethyl-methyl-amide,    [6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-(2-methyl-pyrrolidin-1-yl)-methanone,    6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid tert-butylamide,    6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid cyclopropylmethyl-propyl-amide,    6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-(2-methyl-piperidin-1-yl)-methanone,    (4-hydroxy-piperidin-1-yl)-[6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-methanone,    [6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-(3-methyl-piperidin-1-yl)-methanone,    (3,4-dihydro-1H-isoquinolin-2-yl)-[6-(3-piperidin-1-yl-propoxy)-naphthalen-2-yl]-methanone 1:1 hydrochloride,    [6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-thiomorpholin-4-yl-methanone,    [6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-(2-trifluoromethyl-pyrrolidin-1-yl)-methanone,    6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid ethyl-(2-methoxy-ethyl)-amide,    azetidin-1-yl-[6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-methanone,    (3,6-dihydro-2H-pyridin-1-yl)-[6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-methanone,    6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid (3-fluoro-oxetan-3-ylmethyl)-amide,    6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid (1-methoxymethyl-cyclopropylmethyl)-amide,    {6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid [2-(tetrahydro-pyran-4-yl)-ethyl]-amide,    [6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-morpholin-4-yl-methanone,    6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid cyclohexyl-methyl-amide,    (4,4-difluoro-piperidin-1-yl)-[6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-methanone,    (3-hydroxy-pyrrolidin-1-yl)-[6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-methanone,    [6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-pyrrolidin-1-yl-methanone,    (R)-1-[6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carbonyl]-pyrrolidine-2-carbonitrile,    (1,1-dioxo-thiomorpholin-4-yl)-[6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-methanone,    6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid dimethylamide    (2,5-dihydro-pyrrol-1-yl)-[6-(1-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-methanone,    ([6-(1-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-(4-methoxy-piperidin-1-yl)-methanone,    6-(1-isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid ethyl-methyl-amide,    ([6-(1-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-(4-methyl-piperidin-1-yl)-methanone,    [6-(1-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-(2-methyl-pyrrolidin-1-yl)-methanone,    6-(1-isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid tert-butylamide,    6-(1-isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid cyclopropylmethyl-propyl-amide,    {[6-(1-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-(2-methyl-piperidin-1-yl)-methanone,    [6-(1-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-(3-methyl-piperidin-1-yl)-methanone,    6-(1-isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid isopropyl-methyl-amide,    [6-(1-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-thiomorpholin-4-yl-methanone,    [6-(1-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-(2-trifluoromethyl-pyrrolidin-1-yl)-methanone,    6-(1-isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid ethyl-(2-methoxy-ethyl)-amide,    azetidin-1-yl-[6-(1-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-methanone,    (3,6-dihydro-2H-pyridin-1-yl)-[6-(1-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-methanone,    6-(1-isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid (3-fluoro-oxetan-3-ylmethyl)-amide,    6-(1-isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid (1-methoxymethyl-cyclopropylmethyl)-amide,    6-(1-isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid [2-(tetrahydro-pyran-4-yl)-ethyl]-amide,    (4,4-difluoro-piperidin-1-yl)-[6-(1-isopropyl-pyrrolidin-3-yloxy)-quinolin-2-yl]-methanone,    [6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-morpholin-4-yl-methanone,    (4-methoxy-piperidin-1-yl)-[6-(3-piperidin-1-yl-propoxy)-quinolin-2-yl]-methanone,    (4-methyl-piperidin-1-yl)-[6-(3-piperidin-1-yl-propoxy)-quinolin-2-yl]-methanone    morpholin-4-yl-[6-(3-piperidin-1-yl-propoxy)-quinolin-2-yl]-methanone,    (2-methyl-pyrrolidin-1-yl)-[6-(3-piperidin-1-yl-propoxy)-quinolin-2-yl]-methanone,    6-(3-piperidin-1-yl-propoxy)-quinoline-2-carboxylic acid cyclopropylmethyl-propyl-amide,    [6-(3-piperidin-1-yl-propoxy)-quinolin-2-yl]-(2-trifluoromethyl-pyrrolidin-1-yl)-methanone,    (2,5-dihydro-pyrrol-1-yl)-[6-(3-piperidin-1-yl-propoxy)-quinolin-2-yl]-methanone,    6-(3-piperidin-1-yl-propoxy)-quinoline-2-carboxylic acid ethyl-(2-methoxy-ethyl)-amide,    azetidin-1-yl-[6-(3-piperidin-1-yl-propoxy)-quinolin-2-yl]-methanone,    (3,6-dihydro-2H-pyridin-1-yl)-[6-(3-piperidin-1-yl-propoxy)-quinolin-2-yl]-methanone,    (4,4-difluoro-piperidin-1-yl)-[6-(3-piperidin-1-yl-propoxy)-quinolin-2-yl]-methanone,    6-(3-piperidin-1-yl-propoxy)-quinoline-2-carboxylic acid cyclohexyl-methyl-amide,    6-(3-piperidin-1-yl-propoxy)-quinoline-2-carboxylic acid (1-methoxymethyl-cyclopropylmethyl)-amide,    6-(3-piperidin-1-yl-propoxy)-quinoline-2-carboxylic acid (3-fluoro-oxetan-3-ylmethyl)-amide,    6-(3-piperidin-1-yl-propoxy)-quinoline-2-carboxylic acid [2-(tetrahydro-pyran-4-yl)-ethyl]-amide,    6-(3-piperidin-1-yl-propoxy)-quinoline-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide,    (2-methyl-piperidin-1-yl)-[6-(3-piperidin-1-yl-propoxy)-quinolin-2-yl]-methanone,    [6-(3-piperidin-1-yl-propoxy)-quinolin-2-yl]-pyrrolidin-1-yl-methanone,    (R)-1-[6-(3-piperidin-1-yl-propoxy)-quinoline-2-carbonyl]-pyrrolidine-2-carbonitrile,    (1,1-dioxo-thiomorpholin-4-yl)-[6-(3-piperidin-1-yl-propoxy)-quinolin-2-yl]-methanone,    (4-methyl-piperidin-1-yl)-{6-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-quinolin-2-yl}-methanone,    {6-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-quinolin-2-yl}-pyrrolidin-1-yl-methanone,    (R)-1-{6-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-quinoline-2-carbonyl}-pyrrolidine-2-carbonitrile,    (1,1-dioxo-thiomorpholin-4-yl)-{6-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-quinolin-2-yl}-methanone,    (4-methoxy-piperidin-1-yl)-{6-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-quinolin-2-yl}-methanone,    {6-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-quinolin-2-yl}-morpholin-4-yl-methanone,    azetidin-1-yl-{6-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-quinolin-2-yl}-methanone,    6-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-quinoline-2-carboxylic acid [2-(tetrahydro-pyran-4-yl)-ethyl]-amide,    6-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-quinoline-2-carboxylic acid (3-fluoro-oxetan-3-ylmethyl)-amide,    (2-methyl-pyrrolidin-1-yl)-{6-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-quinolin-2-yl}-methanone,    (S)-1-[6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carbonyl]-pyrrolidine-2-carbonitrile,    [6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-(4-methyl-piperidin-1-yl)-methanone,    (4-hydroxymethyl-piperidin-1-yl)-[6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-methanone,    6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid isobutyl-amide,    6-(1-isopropyl-pyrrolidin-3-yloxy)-quinoline-2-carboxylic acid cyclohexyl-methyl-amide,and pharmaceutically acceptable salts thereof.
Particularly preferred compounds of formula I of the present invention are the following:    [6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-(4-methoxy-piperidin-1-yl)-methanone,    [6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-(2-methyl-pyrrolidin-1-yl)-methanone,    [6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-(2-trifluoromethyl-pyrrolidin-1-yl)-methanone,    azetidin-1-yl-[6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-methanone,    6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid (3-fluoro-oxetan-3-ylmethyl)-amide,    6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid (1-methoxymethyl-cyclopropylmethyl)-amide,    [6-(1-isopropyl-piperidin-4-yloxy)-quinolin-2-yl]-pyrrolidin-1-yl-methanone,    (R)-1-[6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carbonyl]-pyrrolidine-2-carbonitrile,    azetidin-1-yl-[6-(3-piperidin-1-yl-propoxy)-quinolin-2-yl]-methanone,    (R)-1-[6-(3-piperidin-1-yl-propoxy)-quinoline-2-carbonyl]-pyrrolidine-2-carbonitrile,    (S)-1-[6-(1-isopropyl-piperidin-4-yloxy)-quinoline-2-carbonyl]-pyrrolidine-2-carbonitrile,and pharmaceutically acceptable salts thereof.
Furthermore, the pharmaceutically acceptable salts of the compounds of formula I and the pharmaceutically acceptable esters of the compounds of formula I individually constitute preferred embodiments of the present invention.
Compounds of formula I may form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, salicylate, sulphate, pyruvate, citrate, lactate, mandelate, tartrate, and methanesulphonate. Preferred are the hydrochloride salts. Also solvates and hydrates of compounds of formula I and their salts form part of the present invention.
Compounds of formula I can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. The optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbens or eluant). The invention embraces all of these forms.
It will be appreciated, that the compounds of general formula I in this invention may be derivatized at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo. Physiologically acceptable and metabolically labile derivatives, which are capable of producing the parent compounds of general formula I in vivo are also within the scope of this invention.
A further aspect of the present invention is the process for the manufacture of compounds of formula I as defined above, which process comprises reacting a compound of the formula II
wherein R is lower alkyl,with an alcohol of the formula IIIHO-A  IIIwherein A is as defined herein before,in the presence of a trialkylphosphine or triphenylphosphine and of a diazo compound to obtain a compound of the formula IV
and converting the ester of formula IV into the acid of formula V
under acidic or basic conditions,and coupling the compound of formula V with an amine of the formula VIH—NR1R2  VIwherein R1 and R2 are as defined herein before, with the help of an coupling agent under basic conditions to obtain a compound of the formula I
wherein A, R1 and R2 are as defined herein before,and if desired,converting the compound obtained into a pharmaceutically acceptable salt.
Coupling agents for the reaction of compounds of formula V with amines of formula VI are for example N,N′-carbonyldiimidazole (CDI), N,N′-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT), or O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU).
In more detail, the compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the text or in the examples, or by methods known in the art.

Compounds of formula II can be manufactured starting from commercially available 6-methoxy-quinoline (1) that can converted to the N-oxide 2 by reaction with hydrogen peroxide and a solvent like acetic acid under refluxing conditions. The 6-methoxy-quinoline-1-oxide is reacted with silver cyanide and benzoyl chloride to obtain the 6-methoxy-quinoline-2-carbonitrile 3 via a modification of the Reisset'sche reaction (Ber., 38, 1610 (1905). Hydrolysis of the cyano group can be affected by employing an acidic or basic medium. We find it convenient to use a base like sodium hydroxide and after acidic treatment of the mixture we obtained the corresponding 6-methoxy-quinoline-2-carboxylic acid 4. Removal of the methyl group with an acid like hydrobromic acid 48% in water gives 6-hydroxy-quinoline-2-carboxylic acid (5). The acid can be esterified with an alcohol like ethanol and an acid like sulfuric acid to yield the 6-hydroxy-quinoline-2-carboxylic acid ester II, for example 6-hydroxy-quinoline-2-carboxylic acid ethyl ester (IIa).
The preparation of compounds of formula I of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following scheme. The skills required for carrying out the reaction and purification of the resulting products are known to those in the art. The substituents and indices used in the following description of the processes have the significance given above unless indicated to the contrary.

Compounds of general formula I can be prepared according to scheme 2 as follows:    a) The syntheses of ethers are widely described in literature and the procedures are known to those in the art (For reaction conditions described in literature affecting such reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, 1999). The transformation can be affected by employing reaction conditions which are commonly utilised in the so called “Mitsunobu reaction” which is known to those in the art and widely described (Hughes, David L. The Mitsunobu reaction. Organic Reactions (John Wiley & Sons, New York, 1992, 42, 335-656) We find it convenient to couple an ester of formula II with alcohols of formula III (either commercially available or accessible by methods described in references or by methods known in the art; as appropriate) under conditions employing a phosphine like a trialkylphosphine such as tributylphosphine ((n-Bu)3,P), triphenylphosphine (Ph3P) and the like and a diazo-compound like diethyl-azodicarboxylate (DEAD), diisopropyl-azodicarboxylate (DIAD) (optionally polymer bound), tetramethyl azodicarboxamide and the like in a solvent commonly used in such transformations like tetrahydrofurane (THF), toluene, dichloromethane and the like. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield the compounds of formula IV.    b) The hydrolysis of esters are widely described in literature and the procedures are known to those in the art (For reaction conditions described in literature affecting such reactions see for example:). The transformation can be affected by employing acidic or basic medium. We find it convenient to use acidic conditions employing an acid like HCl and a solvent like dioxane, THF and the like. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield the title compounds VI.    c) The coupling of carboxylic acids with amines is widely described in literature and the procedures are known to those in the art (For reaction conditions described in literature affecting such reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, 1999). 6-Alkoxy-quinoline-2-carboxylic acids of formula IV can conveniently be transformed to the respective amide through coupling with an amine V (either commercially available or accessible by methods described in references or by methods known in the art; as appropriate) by employing the usage of coupling agents. For example coupling agents like N,N′-carbonyldiimidazole (CDI), N,N′-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and the like can equally Well be employed to affect such transformation. We find it convenient to carry out the reaction in a solvent like dimethylformamide (DMF) and in the presence of a base. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include: DMF, dichloromethane (DCM), dioxane, THF, and the like. There is no particular restriction on the nature of the base used in this stage, and any base commonly used in this type of reaction may equally be employed here. Examples of such bases include triethylamine and diisopropylethylamine, and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield amide derivatives of formula I.
As described above, the compounds of formula I of the present invention can be used as medicaments for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors. Examples of such diseases are obesity, metabolic syndrome (syndrome X), neurological diseases including Alzheimer's disease, dementia, age-related memory dysfunction, mild cognitive impairment, cognitive deficit, attention deficit hyperactivity disorder, epilepsy, neuropathic pain, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke, dizziness, schizophrenia, depression, addiction, motion sickness and sleep disorders including narcolepsy, and other diseases including asthma, allergy, allergy-induced airway responses, congestion, chronic obstructive pulmonary disease and gastro-intestinal disorders. The use as medicament for the treatment and/or prevention of obesity is preferred.
The invention therefore also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant.
Further, the invention relates to compounds as defined above for use as therapeutically active substances, particularly as therapeutic active substances for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors. Examples of such diseases are obesity, metabolic syndrome (syndrome X), neurological diseases including Alzheimer's disease, dementia, age-related memory dysfunction, mild cognitive impairment, cognitive deficit, attention deficit hyperactivity disorder, epilepsy, neuropathic pain, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke, dizziness, schizophrenia, depression, addiction, motion sickness and sleep disorders including narcolepsy, and other diseases including asthma, allergy, allergy-induced airway responses, congestion, chronic obstructive pulmonary disease and gastro-intestinal disorders.
In another embodiment, the invention relates to a method for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors. Examples of such diseases are obesity, metabolic syndrome (syndrome X), neurological diseases including Alzheimer's disease, dementia, age-related memory dysfunction, mild cognitive impairment, cognitive deficit, attention deficit hyperactivity disorder, epilepsy, neuropathic pain, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke, dizziness, schizophrenia, depression, addiction, motion sickness and sleep disorders including narcolepsy, and other diseases including asthma, allergy, allergy-induced airway responses, congestion, chronic obstructive pulmonary disease and gastrointestinal disorders. A method for the treatment and/or prevention of obesity is preferred.
The invention further relates to the use of compounds of formula I as defined above for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors. Examples of such diseases are obesity, metabolic syndrome (syndrome X), neurological diseases including Alzheimer's disease, dementia, age-related memory dysfunction, mild cognitive impairment, cognitive deficit, attention deficit hyperactivity disorder, epilepsy, neuropathic pain, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke, dizziness, schizophrenia, depression, addiction, motion sickness and sleep disorders including narcolepsy, and other diseases including asthma, allergy, allergy-induced airway responses, congestion, chronic obstructive pulmonary disease and gastro-intestinal disorders. The use of compounds of formula I as defined above for the treatment and/or prevention of obesity is preferred.
In addition, the invention relates to the use of compounds of formula I as defined above for the preparation of medicaments for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors. Examples of such diseases are obesity, metabolic syndrome (syndrome X), neurological diseases including Alzheimer's disease, dementia, age-related memory dysfunction, mild cognitive impairment, cognitive deficit, attention deficit hyperactivity disorder, epilepsy, neuropathic pain, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke, dizziness, schizophrenia, depression, addiction, motion sickness and sleep disorders including narcolepsy, and other diseases including asthma, allergy, allergy-induced airway responses, congestion, chronic obstructive pulmonary disease and gastro-intestinal disorders. The use of compounds of formula I as defined above for the preparation of medicaments for the treatment and/or prevention of obesity is preferred.
The compounds of formula I and their pharmaceutically acceptable salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention are good histamine 3 receptor (H3R) antagonists and/or inverse agonists.
The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be used as medicaments, e.g. in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils.
The production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula (I) and their pharmaceutically acceptable, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragées and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers are, however, required in the case of soft gelatine capsules). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
Usual stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavor-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
The dosage of the compounds of formula (I) can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage of about 1 mg to about 1000 mg, especially about 1 mg to about 100 mg, comes into consideration. Depending on the dosage it is convenient to administer the daily dosage in several dosage units.
The pharmaceutical preparations conveniently contain about 0.1-500 mg, preferably 0.5-100 mg, of a compound of formula (I).
The following examples serve to illustrate the present invention in more detail. They are, however, not intended to limit its scope in any manner.